Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition characterized by hyperactivity, inattention and impulsivity, typically in school-aged boys. Psychostimulants, including methylphenidate and amphetamines, are commonly used to alleviate symptoms of ADHD. However, these medications are typically associated with undesirable side effects, prompting the search for novel non-psycho stimulant treatments for ADHD. Salient features of clinical ADHD are commonly modeled in juvenile rats following neonatal lesioning with 6-hydroxy-dopamine (6-OHDA). Such rats exhibit several characteristics resembling symptoms of ADHD, most notably, motor hyperactivity that occurs selectively during the periadolescent period, and can be dose-dependently antagonized by psychostimulants. A major recent discovery from our laboratory is that the locomotor hyperactivity associated with neonatal dopamine (DA) lesioning was reversed in dose-dependent manner by a highly selective DA D4 receptor antagonist (CP-293,019), and worsened by a D4 agonist (CP-226,269). These findings accord with a repeatedly reported genetic association of D4 receptor alleles and ADHD, and implicate D4 receptors as attractive targets for innovative treatments for ADHD. This project includes further chemical, pharmacological and behavioral characterization of the neonatal 6-OHDA-lesion-hyperactivity model. Several novel D4 compounds will be chemically synthesized using our proprietary N-benzyl-4- phenylpiperidines to optimize their D4 antagonist activity. This will be accomplished by modifying the piperidine pharmacophore, the N-benzyl substituent, or the phenyl substituent to exploit the rich structure-activity relationships available for increased potency and/or selectivity for the D4 receptor subtype. The pharmacological profile of these compounds will be characterized by determining their affinity to D4 receptors and other DA and serotonin receptor subtypes, as well as their molecular functionality at D4 receptors. The behavioral effects of novel selected compounds that display full D4 antagonistic properties will be assessed in juvenile hyperactive rats and their sham-control littermates to determine their efficacy in reversing locomotor hyperactivity. Expected findings should evolve new principles and lead to novel compounds that can be used as much-needed innovative treatments for ADHD and other major neuropsychiatric disorders.